Effect of a facemask leak on aerosol delivery from a pMDI-spacer system.

The objective of this investigation was to study the relation between size and position of a mask leak on spacer output and lung dose. An upper-airway model (SAINT model, Erasmus MC) was connected to a breathing simulator. Facemasks with leaks ranging between 0 and 1.5 cm(2) were examined. Leaks were located close to the nose or close to the chin. During simulated breathing, 200 microg budesonide (Pulmicort, AstraZeneca) was delivered to the model via NebuChamber (AstraZeneca) with facemask. Spacer output and lung dose were measured by placing a filter between spacer and facemask or between model and breathing simulator, respectively. Budesonide trapped on the filter was quantified by means of HPLC, and expressed as percentage of the nominal dose. Mean spacer output doses for the nose position were 50, 38, 28, 12, 10, 6, and 0%, and for the chin position were 50, 40, 31, 11, 9, 4, and 0% for leaks of 0, 0.05, 0.1, 0.16, 0.2, 0.3, and larger than 0.4 cm(2), respectively. Mean lung doses for the nose position were 10, 8, 6, 3, 3, 1, 0, 0, 0, and 0%, and for the chin position were 10, 9, 8, 6, 6, 5, 1, 1, 0, and 0% for leaks of 0, 0.05, 0.1, 0.16, 0.2, 0.3, 0.4, 0.5, 1, and 1.5 cm(2). Efficiency of a pMDI-spacer facemask strongly depends on the size of a facemask leak. Spacer output did not depend on the position of the leak. Lung dose was higher for leaks near the chin than for leaks near the nose.

Effect of series of resistance levels on flow limitation in mechanically ventilated COPD patients.

In severe chronic obstructive pulmonary disease (COPD) lung emptying is disturbed by airways compression and expiratory flow limitation. Application of an external resistance has been suggested to counteract airways compression and improve lung emptying. We studied the effect of various resistance levels on lung emptying in mechanically ventilated COPD patients. In 18 patients an adjustable resistor was applied. The effect on airways compression was assessed by iso-volume pressure--flow curves (IVPF) and by interrupter measurements. Respiratory mechanics during unimpeded expirations were correlated to the results obtained with the resistances. The resistances caused an increase in iso-volume flow at the IVPF-curves in six patients, indicating that airways compression was counteracted. Interrupter measurements showed that overshoots in flow (as measure of flow limitation) were significantly reduced by the resistor. These effects could be predicted on basis of respiratory mechanics during unimpeded expiration. In conclusion, mechanically ventilated COPD patients can be identified in whom application of external resistances counteracts airways compression and reduces flow limitation.

A new approach to mechanical simulation of lung behaviour: pressure-controlled and time-related piston movement.

A mechanical lung simulator is described (an extension of a previous mechanical simulator) which simulates normal breathing and artificial ventilation in patients. The extended integration of hardware and software offers many new possibilities and advantages over the former simulator. The properties of components which simulate elastance and airway resistance of the lung are defined in software rather than by the mechanical properties of the components alone. Therefore, a more flexible simulation of non-linear behaviour and the cross-over effects of lung properties is obtained. Furthermore, the range of lung compliance is extended to simulate patients with emphysema. The dependency of airway resistance on lung recoil pressure and transmural pressure of the airways can also be simulated. The new approach enables one to incorporate time-related mechanics such as the influence of lung viscosity or cardiac oscillation. The different relations defined in the software can be changed from breath to breath. Three simulations are presented: (1) computer-controlled expiration in the artificially ventilated lung; (2) simulation of normal breathing; and (3) simulation of viscoelastance and cardiac influences during artificial ventilation. The mechanical simulator provides a reproducible and flexible environment for testing new software and equipment in the lung function laboratory and in intensive care, and can be used for instruction and training.

Estimation of respiratory parameters via fuzzy clustering.

The results of monitoring respiratory parameters estimated from flow-pressure-volume measurements can be used to assess patients' pulmonary condition, to detect poor patient-ventilator interaction and consequently to optimize the ventilator settings. A new method is proposed to obtain detailed information about respiratory parameters without interfering with the expiration. By means of fuzzy clustering, the available data set is partitioned into fuzzy subsets that can be well approximated by linear regression models locally. Parameters of these models are then estimated by least-squares techniques. By analyzing the dependence of these local parameters on the location of the model in the flow-volume-pressure space, information on patients' pulmonary condition can be gained. The effectiveness of the proposed approaches is demonstrated by analyzing the dependence of the expiratory time constant on the volume in patients with chronic obstructive pulmonary disease (COPD) and patients without COPD.

Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients.

STUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the augmented mechanical behavior of the lung. Therefore, we studied the interrelationships between indexes of BHR, on the one hand, and markers of lung parenchymal destruction, on the other. PATIENTS AND METHODS: COPD patients were selected by clinical symptoms, evidence of chronic, nonreversible airways obstruction, and BHR, which was defined as a provocative dose of a substance (histamine) causing a 20% fall in FEV(1) (PC(20)) of

Expiratory time constants in mechanically ventilated patients with and without COPD.

OBJECTIVE: In mechanically ventilated patients, the expiratory time constant provides information about the respiratory mechanics and the actual time needed for complete expiration. As an easy method to determine the time constant, the ratio of exhaled tidal volume to peak expiratory flow has been proposed. This assumes a single compartment model for the whole expiration. Since the latter has to be questioned in patients with chronic obstructive pulmonary disease (COPD), we compared time constants calculated from various parts of expiration and related these to time constants assessed with the interrupter method. DESIGN: Prospective study. SETTING: A medical intensive care unit in a university hospital. PATIENTS: Thirty-eight patients (18 severe COPD, eight mild COPD, 12 other pathologies) were studied during mechanical ventilation under sedation and paralysis. MEASUREMENTS AND RESULTS: Time constants determined from flow-volume curves at 100%, the last 75, 50, and 25% of expired tidal volume, were compared to time constants obtained from interrupter measurements. Furthermore, the time constants were related to the actual time needed for complete expiration and to the patient's pulmonary condition. The time constant determined from the last 75% of the expiratory flow-volume curve (RCfv75) was in closest agreement with the time constant obtained from the interrupter measurement, gave an accurate estimation of the actual time needed for complete expiration, and was discriminative for the severity of COPD. CONCLUSIONS: In mechanically ventilated patients with and without COPD, a time constant can well be calculated from the expiratory flow-volume curve for the last 75% of tidal volume, gives a good estimation of respiratory mechanics, and is easy to obtain at the bedside.

Computer-controlled flow resistance.

A computer-controlled flow resistance (CCR), to be used in a computer-controlled lung model, is presented. Flow is forced through a slit between a cylinder and a sleeve around the cylinder. The resulting flow resistance depends on the width, circumferences and the variable length of the slit. The variation in the length is computer-controlled by the position of the sleeve with respect to the cylinder. The total flow resistance also depends on inlet and outlet resistance at both sides of the slit and on flow. The dependence on flow is primarily due to the shape of the inlet of the slit. The resistance of the slit itself is almost independent of flow. The resistance is calculated during a calibration phase at different positions of the sleeve, for flow values from 0.05 to 1.0 litre.s-1 (inflow) and from -0.05 to -1.0 litre.s-1 (outflow). To simulate a required resistance pattern, as, for instance, will occur during breathing, at each moment the set position of the sleeve is calculated by means of an interpolation from the relationship between flow resistance and position of the sleeve. The internal diameter of the sleeve is fixed. To tune the resistance range for a specific simulation, the cylinder is changed for one with different diameter, changing the width of the slit.

Effect of a nasal dilatator on nasal patency during normal and forced nasal breathing.

A nasal dilatator contains two elastic strips, which provide the dilatator with a spring action. The aimed function of the nasal dilatator is to slightly open the nares and hereby facilitate nasal breathing. The aim of this study was to evaluate the effect of a nasal dilatator by measuring nasal airway resistance during normal breathing and nasal forced expiratory and inspiratory flows and volumes with and without use of the nasal dilatator. Nasal resistance was measured with a whole body plethysmograph; maximal expiratory and inspiratory flow-volume curves were obtained with a pneumotachometer. These measurements were performed in ten healthy volunteers. No significant difference was found between nasal resistance with and without the nasal dilatator. However, values for forced inspiratory volume in 1 s (FIV 1) with the nasal dilatator, proved to be significantly higher (p=0.045,paired t-test) than values obtained without the nasal dilatator; mean improvement was 0.26 L (sd = 0.36). No significant improvement in peak inspiratory flow (PIF) was found, as was the case for the other flows and volumes. It is concluded that the nasal dilatator causes no appreciable improvement of nasal patency during normal breathing. In view of the fact that FIV 1 values increased significantly, we believe that the nasal dilatator prevents collapse of the external nares during forced inspiration. A beneficial effect during exercise when ventilation is increased is however doubtful because in that situation most volunteers switch to oronasal breathing already at submaximal exercise.

Dead space and slope indices from the expiratory carbon dioxide tension-volume curve.

The slope of phase 3 and three noninvasively determined dead space estimates derived from the expiratory carbon dioxide tension (PCO2) versus volume curve, including the Bohr dead space (VD,Bohr), the Fowler dead space (VD,Fowler) and pre-interface expirate (PIE), were investigated in 28 healthy control subjects, 12 asthma and 29 emphysema patients (20 severely obstructed and nine moderately obstructed) with the aim to establish diagnostic value. Because breath volume and frequency are closely related to CO2 elimination, the recording procedures included varying breath volumes in all subjects during self-chosen/natural breathing frequency, and fixed frequencies of 10, 15 and 20 breaths x min(-1) with varying breath volumes only in the healthy controls. From the relationships of the variables with tidal volume (VT), the values at 1 L were estimated to compare the groups. The slopes of phase 3 and VD,Bohr at 1 L VT showed the most significant difference between controls and patients with asthma or emphysema, compared to the other two dead space estimates, and were related to the degree of airways obstruction. Discrimination between no-emphysema (asthma and controls) and emphysema patients was possible on the basis of a plot of intercept and slope of the relationship between VD,Bohr and VT. A combination of both the slope of phase 3 and VD,Bohr of a breath of 1 L was equally discriminating. The influence of fixed frequencies in the controls did not change the results. The conclusion is that Bohr dead space in relation to tidal volume seems to have diagnostic properties separating patients with asthma from patients with emphysema with the same degree of airways obstruction. Equally discriminating was a combination of both phase 3 and Bohr dead space of a breath of 1 L. The different pathophysiological mechanisms in asthma and emphysema leading to airways obstruction are probably responsible for these results.

Elastic work of breathing during continuous positive airway pressure in intubated patients with chronic obstructive pulmonary disease (theoretical analysis and experimental validation).

BACKGROUND: Continuous positive airway pressure (CPAP) is known to decrease inspiratory work of breathing in patients with chronic obstructive pulmonary disease (COPD). This effect is primarily attributed to a reduction in inspiratory elastic work of breathing (Wi,el) related to a decrease in intrinsic positive end-expiratory pressure (PEEP). METHODS: The aim of this study is to design a model for computation of Wi,el on the basis of respiratory mechanics in patients with COPD, at various intrinsic PEEP- and CPAP-levels. The model was used to estimate the optimal CPAP-level with respect to the intrinsic PEEP-level in terms of reduction of Wi,el. Calculations of the decrease in Wi,el due to CPAP obtained with the model were compared to changes in Wi,el and total work of breathing (Wi,tot) determined from respiratory measurements in patients with COPD. RESULTS: Model calculations revealed that Wi,el was minimal whenever a CPAP-level equal to the intrinsic PEEP-level was applied. When a CPAP-level exceeding the intrinsic PEEP-level was applied, the reduction in Wi,el was less. Comparing these results to the respiratory measurements, a similar pattern in reduction of Wi,el and Wi,tot was established, although absolute values of the differences were smaller in the experimental data. CONCLUSION: This study indicates that in order to reduce Wi,el in patients with COPD, intrinsic PEEP should be measured and the CPAP-level adjusted to the intrinsic PEEP-level.

Breathing pattern awake and asleep in myotonic dystrophy.

Because myotonic dystrophy patients show marked irregularities of breathing both awake and asleep, variables related to breathing pattern under both conditions were measured in 11 patients, together with pulmonary function indices, ventilatory CO2 response and maximal mouth pressures. The aim of the study was to detect and explain a possible interrelationship between daytime and nocturnal irregularity. Awake, patients demonstrated significantly more variability in tidal volume and respiratory cycle time than controls. Asleep, periodic breathing occurred during up to 100% of the time spent in light sleep, but not during deep sleep. A strong correlation was found with age (r = 0.73, p = 0.01). No relationship was found between disturbed breathing awake and asleep. There was a tendency for increased variability of tidal volume awake in cases with a decreased ventilatory CO2 response (p = 0.1). The results indicate that different mechanisms may be involved in daytime and nocturnal irregularity. It is hypothesized that brain stem integrative functions may be impaired in myotonic dystrophy.

Computer-controlled mechanical lung model for application in pulmonary function studies.

A computer controlled mechanical lung model has been developed for testing lung function equipment, validation of computer programs and simulation of impaired pulmonary mechanics. The construction, function and some applications are described. The physical model is constructed from two bellows and a pipe system representing the alveolar lung compartments of both lungs and airways, respectively. The bellows are surrounded by water simulating pleural and interstitial space. Volume changes of the bellows are accomplished via the fluid by a piston. The piston is driven by a servo-controlled electrical motor whose input is generated by a microcomputer. A wide range of breathing patterns can be simulated. The pipe system representing the trachea connects both bellows to the ambient air and is provided with exchangeable parts with known resistance. A compressible element (CE) can be inserted into the pipe system. The fluid-filled space around the CE is connected with the water compartment around the bellows; The CE is made from a stretched Penrose drain. The outlet of the pipe system can be interrupted at the command of an external microcomputer system. An automatic sequence of measurements can be programmed and is executed without the interaction of a technician.

Detection of flow limitation during tidal breathing by the interruptor technique.

In patients with airflow obstruction, flow limitation can be established in various ways. Using body plethysmography, flow limitation is assumed when expiratory flow decreases whilst alveolar pressure increases at the same time. During forced expiration, flow limitation can be established by means of the flow interruptor technique; flow limitation is assumed when, after release of an occlusion, a spike flow superimposed on the ongoing alveolar flow (delta peak flow) is detected. In this study, the flow interruptor technique was applied to detect flow limitation during tidal breathing. The results were compared to those obtained with the body plethysmograph. The expiratory flow pattern, post-interruption, was analysed in 33 subjects; 11 patients with airflow obstruction and flow limitation established with the body plethysmograph (AO+); 11 patients with airflow obstruction without flow limitation (AO-); and 11 healthy volunteers. Mean spike areas were 27.6 +/- 18.3, 4.6 +/- 2.3 and 3.4 +/- 2.0 mL for the AO+, AO- and control group, respectively, showing a highly significant difference between the AO+ patients and the other groups. Also, significantly higher delta peak flows were found in the AO+ patients compared to the other groups. No differences in delta peak flows or spike areas could be established between patients without flow limitation and controls. We conclude that the interruptor technique may be a useful means of assessing flow limitation during tidal breathing.

Pressure-volume analysis of the lung with an exponential and linear-exponential model in asthma and COPD. Dutch CNSLD Study Group.

The prevalence of abnormalities in lung elasticity in patients with asthma or chronic obstructive pulmonary disease (COPD) is still unclear. This might be due to uncertainties concerning the method of analysis of quasistatic deflation lung pressure-volume curves. Pressure-volume curves were obtained in 99 patients with moderately severe asthma or COPD. These patients were a subgroup from a Dutch multicentre trial; the entire group was selected on the basis of a moderately lowered % predicted forced expiratory volume in one second (FEV1), and a provocative concentration of histamine producing a 20% decrease in FEV1 (PC20) < 8 mg.mL-1 obtained with the 2 min tidal breathing technique. The curves were fitted with an exponential (E) model and an exponential model which took the linear appearance in the mid vital capacity range into account (linear-exponential (LE)). The linear-exponential model showed a markedly better fit ability, yielding additional parameters, such as the compliance at functional residual capacity (FRC) level as slope of the linear part (b), and the volume at which the linear part changed into the exponential part of the curve (transition volume (Vtr)). Vtr (mean value Vtr/total lung capacity (TLC) = 0.79 (SD 0.07)) showed a close positive linear correlation with obstruction and hyperinflation variables, which might be due to airway closure, already starting at elevated lung volumes. The exponential shape factor K was closely correlated with b and mean values (K = 1.32 (SD 0.05) kPa-1; b = 2.96 (SD 1.16) L,kPa-1) and the relationship with age was comparable with data reported in healthy individuals. The shape factor of the linear-exponential fit showed no correlation with any elasticity related variable. Neither the elastic recoil at 90% TLC, as obtained from the linear-exponential fit, nor its relationship with age were significantly different from healthy individuals. We conclude that, for a more accurate description of the lung pressure-volume curve, a linear-exponential fit is preferable to an exponential model. However, the physiological relevance of the shape parameter (KLE) is still unclear. These results indicate that patients with moderately severe asthma or COPD had, on average, no appreciable loss of elastic lung recoil as compared with healthy individuals.

Does phase 2 of the expiratory PCO2 versus volume curve have diagnostic value in emphysema patients?

It has been postulated that serial inhomogeneity of ventilation in the peripheral airways in emphysema is represented by the shape of expiratory carbon dioxide tension versus volume curve. We examined the diagnostic value of this test in patients with various degrees of emphysema. The volumes between 25-50% (V25-50) and 25-75% (V25-75) of the expiratory carbon dioxide tension versus volume curve were determined in 29 emphysematous patients (20 severely obstructed and 9 moderately obstructed), 12 asthma patients in exacerbation of symptoms, and 28 healthy controls. Discriminant analysis was used to examine whether these diagnostic groups could be separated. With regard to phase 2 of the expiratory CO2 versus volume curve (mixture of anatomic deadspace and alveolar air), a plot of intercept versus slope of the relationships of (V25-50) and (V25-75) versus inspiratory volume (VI) from functional residual capacity (FRC), obtained during natural breathing frequency, proved to be most discriminating in the separation between healthy controls and severely obstructed emphysema patients. Separating healthy controls and severely obstructed emphysema patients on the basis of the discriminant line for V25-50, 9 of the 12 asthma patients in exacerbation were classified as normal, and only 5 of the 9 moderately obstructed emphysema patients as emphysematous. For V25-75 involvement of phase 3 of the curve (alveolar plateau) in asthma patients in exacerbation caused a marked overlap with the severely obstructed emphysema patients. In the healthy controls, a fixed breathing frequency of 20 breaths.min-1 led to an increase of both volumes.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrapolation of methacholine log-dose response curves with a Cumulative Gaussian Distribution function.

Methacholine provocation tests are aimed at determining bronchial responsiveness. Recent investigations stress the importance of considering the entire log-dose response curve, yielding not only the provocative dose producing a 20% change in forced expiratory volume in one second (FEV1) (PC20), but also the plateau value and the steepest slope of the curve (reactivity). In three control subjects and seven patients with mild to moderate asthma, we have obtained methacholine log-dose response curves in which a plateau was reached. A new model, the Cumulative Gaussian Distribution (CGD) function was fitted to the whole curve. The upper part of the curve was also analysed with the Hofstee equation, which has been used in a number of other investigations and aimed at plateau estimation. The plateau values obtained by the fits were compared with the values actually measured (average response of last 3 points with a variation coefficient < 5% of the mean value) by using the coefficient of determination (R2) (Applied Statistics. Sachs). If all data points were considered, both fits yielded a plateau which slightly overestimated the measured plateau values. R2 for the CGD fit ranged from 0.93-0.99, indicating a highly significant correlation between actual and fitted data points. If the curves were truncated, such that the last four provocative doses were omitted from the analysis, the CGD fit still yielded plateau values; the mean difference from the measured plateaux, in % of the measured plateau values, was -2.6% (SD 18.2). In only three out of the 10 cases did the Hofstee equation yield plateau values with a deviation from 'measured' < 47% of the measured value.(ABSTRACT TRUNCATED AT 250 WORDS)

A quasi steady state ramp method for the estimation of the ventilatory response to CO2.

There are two suitable methods for estimating the ventilatory response to CO2: the steady state or the Read method. The latter is usually applied because of its shorter duration and its stimulus, near to tissue PCO2. From recent studies on a physiological model but also on the dynamics of the ventilatory CO2 response (G liters min-1 kPa-1), it can be shown, both theoretically and experimentally, that the Read method markedly overestimates the steady-state estimate of the ventilatory CO2 response (Gss). We have, therefore, applied two ramp approaches: one with an initial end-tidal PCO2 (PetCO2) step of 0.5 kPa and a mean PetCO2 ramp slope of 0.41 kPa/min (step-ramp method, SR) and one without an initial step and a mean ramp slope of 0.21 kPa/min (ramp method; R). As predicted by theory, the ventilatory CO2 response from the R method (GR) during the second 4-min interval of the 8-min procedure and the ventilatory CO2 response from the SR method (GSR) from the whole 6-min procedure, except for the first 30 s, should yield a good approximation of Gss. In a group of 12 normal volunteers we indeed found no differences between these estimates, and, as predicted by theory, we found both estimates to be larger than GR from the first 4-min interval. From the interindividual spread, only the difference with respect to GSR was significant (p less than 0.02). The volunteers preferred the R approach because of the lower PetCO2 attained and the smaller ventilation increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial lung model for simulation and parameter estimation in body plethysmography.

A serial lung model with a compressible segment has been implemented to simulate different types of lung and airway disorders such as asthma, emphysema, fibrosis and upper airway obstruction. The model described can be used during normal breathing, and moreover the compliant segment is structured according to more recent physiological data. A parameter estimation technique was applied and its reliability and uniqueness were tested by means of sine wave input signals. The characteristics of the alveolar pressure/flow patterns simulated with the model agree to a great extent with those found in the literature. In the case of absence of noise the parameter estimation routine produced unique solutions for different simulated pathologic classes. The sensitivity of the different parameters depended on the values belonging to each class of pathology. Some more simplified models are presented and their advantages over the complex model in special types of pathology are demonstrated. Noise added to the simulated flow appeared to have no influence on the estimated parameters, in contradiction to the effects with noise added to the pressure signal. In that case effective resistance was accurately estimated. Where parameters had no influence, as for instance upper airway resistance in emphysema or peripheral airway resistance in upper airway obstruction, the measurement accuracy was less. In all other cases, a satisfactory accuracy could be obtained.

A lung function information system.

A lung function information system (LFIS) was developed for the data analysis of pulmonary function tests at different locations. This system was connected to the hospital information system (HIS) for the retrieval of patient data and the storage of the lung function variables of patients to generate follow-up reports and to support financial and administrative management. The application programs were developed in such a way that high flexibility was obtained with respect to the patient-computer-technician interaction. The sampled data are stored on a disc to correct earlier decisions, perform recalculations and reanalyse the data for research purposes. When the measurements performed on a patient are authorized, the sampled data are deleted, except for when they are needed for future research. A distributed computer system was chosen to combine the benefits of a centralized system with those of several stand-alone systems. The main tasks of the central unit are to store collected data and computer programs, generate a final lung function report on laser printer and provide a connection to the HIS. In the satellite computers, which are located close to the lung function equipment, the signals and raw data are processed. Furthermore, the satellite computers were in use for program development and several research projects, and for the offline data processing of the lung function measurements from two other hospitals by means of a modem connection. The LFIS improved the quantity and quality of data acquisition. It resulted in an increased capacity of about 50% concerning spirometry, and facilitated time-consuming complex analyses. It also avoided miscalculations and mistakes in reports previously experienced with hand calculations.

Dose-effect relationship of terbutaline using a multi-dose powder inhalation system ('Turbuhaler') and salbutamol administered by powder inhalation ('Rotahaler') in asthmatics.

A study was carried out in 8 patients with chronic stable bronchial asthma to compare the bronchodilator response with terbutaline, administered by a recently developed powder inhalation system ('Turbuhaler') and equipotent doses of salbutamol administered by a widely used powder inhaler ('Rotahaler'). Dose-effect relationships with usually applied clinical doses of the bronchodilators were estimated by maximal expiratory flow-volume analysis and airway resistance estimates from body plethysmography. There was no significant difference in clinical response using either inhaler. The equal and opposite changes in forced vital capacity and residual volume with increasing dose indicate an improvement in peripheral airway resistance and, therefore, adequate peripheral powder deposition of the bronchodilators. Only at the highest dose was a mild increase noted in pulse frequency and tremor score with both systems. It is suggested that, because of the multi-dose character, absence of additives, easy handling (no capsule loading) and low inspiratory flow needed for actuation, the 'Turbuhaler' system may be considered preferable for the application of a bronchodilator in children and severely obstructed adults.